Cultured mammalian cells and small nematodes are being used as model systems to study the mechanisms of aging. During the next year, nutrients and regulatory factors that stimulate multiplication of human diploid fibroblasts in a background medium that satisfies all requirements for prolonged survival will be characterized, and age related differences in cellular responses to them will be looked for. High voltage electron microscopy will be used to analyze ultrastructural changes in the microtrabecular lattice of human diploid fibroblasts as they age. Cellular hybrids will be used to study intracellular controls over activation of DNA synthesis in nuclei from normal, senescent, and immortal cells. In particular, the relationship between loss G1 inhibition and the ability to overcome nuclear senescence will be examined. A search for mutant nematodes with altered patterns of aging will be continued, and the mechanisms responsible for an apparent increase in DNA breakage in old nematodes will be examined. The long-term goal of this research program is to understand aging in terms of molecular events occurring within and among the individual cells of aging organisms.